GABAergic Mechanisms of Comorbid Alcohol and Nicotine Dependence

描述（由申请人提供）：酒精依赖和吸烟高度相关，但研究检查潜在的神经化学是稀缺的。在人类中，吸烟似乎在从酒精依赖恢复期间调节GABAA-BZR的可用性。临床数据表明，在酒精依赖的非吸烟者中，在酒精依赖的吸烟者中受到抑制的急性戒断期间，GABAA-BZR的可用性增加。此外，在长时间戒酒期间，GABAA-BZR的可用性似乎降低;但尚未对此进行系统研究。本项目的目的是使用[123 I]iomazenil和单光子发射计算机断层扫描（SPECT）确定长期口服乙醇与长期联合给予乙醇和尼古丁对大脑中GABAA- BZR随时间推移的影响。我们还将检查同时从乙醇和尼古丁戒断期间GABAA-BZR可用性的变化，以及在持续尼古丁暴露的情况下从乙醇戒断期间GABAA-BZR可用性的变化，以研究同时戒烟和戒烟的人中GABAA-BZR的模型变化。我们将获得50只青春期动物的扫描结果（每组n=10）。所有动物将在基线时接受2次扫描，例如，重测第1组将自我给予慢性乙醇24周，并将在停药1天、8天和12周时进行成像。第2组将自我给予慢性尼古丁24周，并将在停药1天、8天和12周时进行成像。组3A将自我给予乙醇加尼古丁24周，并将在停用乙醇和尼古丁后1天、8天和12周进行扫描。第3B组将自我给予乙醇加尼古丁24周，并将在停用乙醇后1天、8天和12周进行成像，但在此停药期内将继续自我给予尼古丁。第4组，对照条件，将自我施用糖精24周，并将在停止糖精后1天、8天和12周进行成像。将进行MRI扫描，以跟踪脑灰质和白色物质以及脑脊液（CSF）的变化。我们假设：1）在急性乙醇戒断期间，与基线和对照组相比，GABAA-BZR的可用性增加，在12周乙醇戒断时，与基线和对照组相比，GABAA-BZR的可用性降低; 2）在尼古丁戒断期间，与基线或对照组相比，GABAA-BZR的可用性没有变化;和3）与单独的乙醇相比，乙醇和尼古丁的组合将导致GABAA-BZR的可用性降低，即，尼古丁将抑制乙醇诱导的增加，并且与同时从乙醇和尼古丁戒断相比，从乙醇戒断到尼古丁存在下将导致对增加的GABAA-BZR可用性的更大抑制。这项研究的结果将促进对酒精和尼古丁依赖的高共病率的神经化学机制的理解，并将对吸烟者和非吸烟者的酒精依赖治疗产生直接的临床意义。公共卫生相关性：拟议的实验将通过描绘大脑机制，GABAA-苯二氮卓受体，直接影响公共卫生，该受体参与酒精依赖的恢复以及酒精依赖和吸烟的相互作用。这些研究将检查酒精和尼古丁的戒断，以确定这些药物对大脑化学的相互作用。这些研究最终将提供如何更成功地治疗这些昂贵的成瘾的信息。

DESCRIPTION (provided by applicant): Alcohol dependence and tobacco smoking are highly associated, yet studies examining the underlying neurochemistry are scarce. In humans, tobacco smoking appears to regulate the availability of the GABAA- BZR during the recovery from alcohol dependence. Clinical data suggest increased GABAA-BZR availability in alcohol dependent nonsmokers during acute withdrawal that is suppressed in alcohol dependent smokers. Additionally, there appears to be decreased GABAA-BZR availability during prolonged alcohol withdrawal; yet this has not been systematically studied. The purpose of this project is to determine the effects of withdrawal from chronic orally-delivered ethanol versus chronic co-administration of ethanol and nicotine on the GABAA- BZR in brain over time using [123I]iomazenil and single photon emission computed tomography (SPECT). We will also examine changes in GABAA-BZR availability during withdrawal from both ethanol and nicotine simultaneously, versus withdrawal from ethanol in the presence of continued nicotine exposure to model changes in GABAA-BZR in humans that quit drinking and smoking simultaneously vs. quitting drinking while continuing to smoke. We will obtain scans in 50 adolescent animals (n=10 per group). All animals will receive 2 scans at baseline, e.g., test-retest. Group 1 will self-administer chronic ethanol for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks withdrawal. Group 2 will self-administer chronic nicotine for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks withdrawal. Group 3A will self-administer ethanol plus nicotine for 24 weeks and will be scanned at 1 day, 8 days and 12 weeks withdrawal from both ethanol and nicotine. Group 3B will self-administer ethanol plus nicotine for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks withdrawal from ethanol, but will continue to self-administer nicotine during this withdrawal period. Group 4, a control condition, will self-administer saccharin for 24 weeks and will be imaged at 1 day, 8 days and 12 weeks after termination of saccharin. MRI scans will be obtained to track changes in brain gray and white matter and cerebrospinal fluid (CSF). We hypothesize that there will be 1) increased GABAA-BZR availability compared to baseline and controls during acute ethanol withdrawal and decreased GABAA-BZR availability compared to baseline and controls at 12 weeks ethanol withdrawal; 2) no change in GABAA-BZR availability compared to baseline or controls during nicotine withdrawal; and, 3) the combination of ethanol and nicotine will result in decreased GABAA-BZR availability compared to ethanol alone, i.e., nicotine will suppress the ethanol-induced increase, and withdrawal from ethanol into the presence of nicotine will result in a greater suppression of increased GABAA-BZR availability compared to withdrawal from ethanol and nicotine simultaneously. The findings from this study will advance the understanding of the neurochemical mechanisms that underlie the high comorbidity of alcohol and nicotine dependence and will have direct clinical implications for the treatment of alcohol dependence in both smokers and nonsmokers. PUBLIC HEALTH RELEVANCE: The proposed experiments will directly impact public health by delineating a brain mechanism, the GABAA- benzodiazepine receptor, which is involved in the recovery from alcohol dependence and in the interaction of alcohol dependence and tobacco smoking. These studies will examine the withdrawal from both alcohol and nicotine to determine the interaction of these drugs on brain chemistry. These studies will ultimately provide information on how to more successfully treat these costly addictions.